Diabetic kidney disease, also known as diabetic nephropathy, is an important cause of excess morbidity and premature mortality in individuals with type 1 diabetes mellitus (T1DM). Approximately 25% to 40% of patients with T1DM ultimately develop diabetic nephropathy. The most serious long-term effect of diabetic nephropathy is kidney failure leading to end stage renal disease (ESRD), a condition in which there is a permanent and almost complete loss of kidney function, with the kidneys functioning at less than 10% of baseline function. Other causes of ESRD include high blood pressure, glomerulonephritis, polycystic kidneys, interstitial disease, obstructive uropathy, systemic lupus erythematosus, and multiple myeloma.
According to prevailing thinking, the development of diabetic nephropathy consists of progression from normoalbuminuria (normal Urinary Albumin Excretion, hereinafter UAE) through three successive clinical stages: 1) microalbuminuria (MA), which is characterized by a small increase in UAE; 2) overt proteinuria, which is characterized by abundant UAE that results in protein over-load of the proximal renal tubules and initiation of renal function loss; and 3) end stage renal disease (ESRD), which requires renal replacement therapy and is coupled with high mortality due to cardiovascular events (Krolewski, et al., Clinical features and epidemiology of diabetic nephropathy. In: Textbook of Diabetes. Second Ed., eds. Pickup and Williams, pp. 53.1-53-13. Oxford: Blackwell Scientific Publications, 1997).
It has been assumed that, as a result of worsening glomerular damage, a large proportion of patients with MA progress to proteinuria. For example, Mauer et al. have emphasized that expansion of the mesangial extracellular matrix in the glomeruli is the major cause of progression of MA to proteinuria and consequently of renal function loss (Mauer et al., J Clin Invest 74:1143-55, 1984). Recently some evidence and many speculations have been put forward emphasizing importance of loss of podocytes (epithelial cells covering the glomeruli) as a mechanism for the development of proteinuria (Lemley et al,. Kidney Int 58:1228-1237, 2000; White et al., Diabetes 51:3083-3089, 2002). It is believed that after patients with T1DM progress to proteinuria, tubular damage begins and leads to tubulointerstitial injury and subsequent fibrosis and loss of renal function (Taft et al., Diabetes 43:1046-51, 1994; Katz et al., Kidney Int 61:2056-66, 2002).